Testosterone Replacement Therapy and Mortality in Older Men

Despite a large prevalence of hypogonadism and increased testosterone prescribing over the past decade1-3, population-based (BACH, Boston Area Community Health)4 and clinical-based studies (HIM, Health In Men)5 report that only 10-12% of hypogonadal patients (comprising 40-45% of studied populations) are receiving treatment.

One important reason for the under-treatment of men with testosterone deficiency is the widespread misperception about testosterone therapy on risk of cardiovascular disease. In this editorial we summarize a review paper by Hackett, which addresses the effects of testosterone therapy on cardiovascular risk factors, as well as mortality.6

Key Points

There is a high level of evidence that hypogonadism is associated with increased all-cause mortality and reduced quality of life.

A large body of evidence shows that testosterone replacement therapy according to expert guidelines is safe and effective for men suffering from testosterone deficiency.

Recent studies suggesting that testosterone replacement therapy may increase cardiovascular risk are severely flawed and do not exclude the possibility that the increased risk is related to hypogonadism and not the testosterone treatment.

What is known

Some well-established benefits of testosterone therapy in hypogonadal men are improvements in sexual function, mood, well-being, muscle mass and bone mineral density.7-9 Testosterone therapy improves body composition and glycometabolic profile, particularly in younger hypogonadal men and in those with metabolic disturbances.9

Despite concerns among clinicians and hypogonadal men, there is no evidence that testosterone therapy is associated with increased risk of prostate cancer10-12 or symptomatic benign prostatic hyperplasia.13 Currently, the main controversy surrounding testosterone therapy is its effect on heart disease.

What this review adds

The controversy about testosterone therapy and its putative negative impact on heart disease is based on a few fundamentally flawed studies.14-17 The review by Hackett points out their methodological problems and concludes that despite suggesting that testosterone therapy may increase cardiovascular risk, these studies do not exclude the possibility that the increased risk is related to hypogonadism and not the testosterone treatment.6 Along the same line, the European Medicines Agency (EMA) concluded that "there is no consistent evidence of increased cardiovascular risk with testosterone products".18 This was based on a European Union-wide review of testosterone medications, which did not find consistent evidence that testosterone therapy in men with hypogonadism increases the risk of heart problems.18

These conclusions are supported by a large body of research evidence from both epidemiological studies and clinical trials, accumulated over several decades. Multiple long-term studies show that hypogonadism is associated with increased cardiovascular and all-cause mortality.19-23 A recent study with a 14-year follow-up suggested a strong association between low baseline testosterone and incident myocardial infarction.24 One meta-analysis of community-based studies found that low testosterone levels at baseline are associated with a 35% and 25% increased risk of all-cause and cardiovascular mortality, respectively, 9 years later.25 The association between low testosterone levels and mortality risk persists even after strict adjustment for comorbidities.

A recent meta-analysis, performed on the largest number of studies collected so far, concludes that testosterone therapy is not related to any increase in cardiovascular risk, and that present data do not support a causal role between testosterone therapy and cardiovascular events.26 In accordance with another more recent meta-analysis9, in subjects with metabolic derangements a protective effect of testosterone therapy on cardiovascular risk is observed.26 This has also been demonstrated in several long-term registry studies lasting up to 8 years, where great improvements where seen in cardiovascular risk factors, including reductions in BMI, waist circumference, LDL, triglycerides, blood pressure, blood glucose, HbA1c and C-reactive protein.27-33

If testosterone was truly bad for the heart – as the flawed studies suggested - one would expect that hypogonadal men with preexisting heart disease would be especially vulnerable to testosterone therapy. To the contrary, several studies show that testosterone therapy in men with chronic heart failure and angina is beneficial. In men with chronic stable angina pectoris, the ischemic threshold increased after 334 and 12 months35 of testosterone therapy. Notably, in the 12 month study, CIMT (a marker of atherosclerosis) tendentially decreased in the testosterone group more than in the placebo group, and the protective effect of testosterone therapy on myocardial ischemia was maintained throughout the 12 month treatment period without decrement.35 In men with chronic heart failure, testosterone therapy increased exercise capacity after 12 weeks36,37, predominantly through improvement in skeletal muscle performance.38

Ultimately, the goal with any medical treatment is to reduce mortality and increase longevity. As of this writing, two prospective studies have demonstrated reduced mortality in men treated with testosterone.20,39 In a study of 1031 men, testosterone treatment was initiated in 398 men (39%) during routine clinical care.20 After a follow-up of 20 months, mortality was 21% among untreated men versus 10% among testosterone treated men, with the greatest mortality reduction in younger men and those with type 2 diabetes.20 The second study of 587 men with type 2 diabetes had a follow-up of 5.8 years. 51 men were treated with testosterone for 2 years or more (mean testosterone therapy duration 3.5 years). Mortality rate was 20% in untreated hypogonadal diabetic men and 8.6 % in hypogonadal diabetic men who received testosterone therapy.39 Both of these studies show that testosterone therapy reduces death by half and increases longevity in treated men.

In summary, the multiple beneficial effects of testosterone therapy can add up to a considerable benefit to the patient that may be underestimated by the physician primarily concerned with his own specialty. Testosterone therapy in hypogonadal men can be a valuable strategy to improve the metabolic profile, reduce body fat and increase muscle mass, which would ultimately reduce the risk of heart disease and increase longevity.